Salt and crystalline forms of rapastinel

Abstract

The application relates to salts of a compound of rapastinel, pharmaceutical compositions thereof, and uses of the salt forms for the treatment of cognitive and neurological diseases and disorders: (Formula I).

1 . Tartrate salt of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
     
     
         2 . A pharmaceutical composition comprising said tartrate salt of a compound of Formula I according to  claim 1  and a pharmaceutical carrier, excipient, adjuvant, or vehicle. 
     
     
         3 . Polymorph form of a tartrate salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       Wherein the polymorphic form is characterized by; an X-ray diffraction pattern comprising (2θ) reflections, plus or minus 0.2 degrees (2θ) at 20.5, 22.8, 25.8, 28.7, 36.8; or an X-ray diffraction pattern substantially as shown in  FIG. 1 . 
     
     
         4 . Polymorph form of a tartrate salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       Characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially the same as shown in  FIG. 2 . 
     
     
         5 . Polymorph form of a tartrate salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       Characterized by a differential scanning calorimetry (DSC) curve substantially the same as shown in  FIG. 3 . 
     
     
         6 . A pharmaceutical composition comprising said polymorphic form of  claim 3 ,  4  or  5  and a pharmaceutical carrier, excipient, adjuvant, or vehicle. 
     
     
         7 . Succinate salt of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A pharmaceutical composition comprising said succinate salt of a compound of Formula I according to  claim 7  and a pharmaceutical carrier, excipient, adjuvant, or vehicle. 
     
     
         9 . Polymorph form of a succinate salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       Wherein the polymorphic form is characterized by; an X-ray diffraction pattern comprising (2θ) reflections, plus or minus 0.2 degrees (2θ) at 14.0, 17.8, 21.6, 26.6, 28.1, 38.6, 29.9; or an X-ray diffraction pattern substantially as shown in  FIG. 4 . 
     
     
         10 . Polymorph form of a succinate salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       Characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially the same as shown in  FIG. 5 . 
     
     
         11 . Polymorph form of a succinate salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       Characterized by a differential scanning calorimetry (DSC) curve substantially the same as shown in  FIG. 6 . 
     
     
         12 . A pharmaceutical composition comprising said polymorphic form of  claim 9 ,  10  or  11  and a pharmaceutical carrier, excipient, adjuvant, or vehicle. 
     
     
         13 . Hydrochloride salt of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A pharmaceutical composition comprising said hydrochloride salt of a compound of Formula I according to  claim 13  and a pharmaceutical carrier, excipient, adjuvant, or vehicle. 
     
     
         15 . Polymorph form of a hydrochloride salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       Wherein the polymorphic form is characterized by; an X-ray diffraction pattern comprising (2θ) reflections, plus or minus 0.2 degrees (2θ) at 18.1, 22.2, 23.3, 31.8; or an X-ray diffraction pattern substantially as shown in  FIG. 7 . 
     
     
         16 . Polymorph form of a hydrochloride salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       Characterized by thermogravimetric analysis (TGA) comprising a thermogram substantially the same as shown in  FIG. 8 . 
     
     
         17 . Polymorph form of a hydrochloride salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
       Characterized by a differential scanning calorimetry (DSC) curve substantially the same as shown in  FIG. 9 . 
     
     
         18 . A pharmaceutical composition comprising said polymorphic form of  claim 15 ,  16  or  17  and a pharmaceutical carrier, excipient, adjuvant, or vehicle. 
     
     
         19 . A method of treating a patient suffering from a cognitive, neurological or psychological disease or disorder comprising the step of administering to said patient a therapeutically effective amount of tartrate, succinate or hydrochloride salt of a compound of Formula I 
       
         
           
           
               
               
           
         
       
     
     
         20 . A method of treating a patient suffering from a cognitive, neurological or psychological disease or disorder comprising the step of administering to said patient a therapeutically effective amount of a tartrate, succinate or hydrochloride salt of a compound of Formula I, according to any of  claims 1 - 18 . 
     
     
         21 . The method according to any of  claims 19 - 20  wherein said cognitive, neurological or psychological disease or disorder is selected from the group consisting of deficiency in memory, intellect, or learning and logic ability; reduction in any particular individual's functioning in one or more cognitive aspects; age-related cognitive decline; dementia; Alzheimer's disease; multi-infarct dementia; alcoholic dementia or other drug-related dementia; dementia associated with intracranial tumors or cerebral trauma; dementia associated with Huntington's disease or Parkinson's disease; AIDS-related dementia; delirium; amnestic disorder; mental retardation; a learning disorder including reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; schizophrenia, schizophrenia including negative symptoms; schizophreniform disorder; schizoaffective disorder, schizoaffective disorder of the delusional type, schizoaffective disorder of the depressive type; delusional disorder; substance-induced psychotic disorder; personality disorder of the paranoid type; personality disorder of the schizoid type; panic disorder; phobias; obsessive-compulsive disorder; stress disorders; generalized anxiety disorder; movement disorders involving Huntington's disease; dyskinesia associated with dopamine agonist therapy: Parkinson's disease: restless leg syndrome; disorders comprising as a symptom thereof a deficiency in cognition. 
     
     
         22 . The method according to any of  claims 19 - 20  wherein said disease or disorder is selected from depression, major depressive disorder, refractory depression, pre-menstrual dysphoric disorder, post-partum depression, acute depressive episodes with bipolar I, treatment resistant depression, general anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, social anxiety disorder, bulimia nervosa, cognitive dysfunction in pre-menstrual dysphoric disorder, attention deficit hyperactivity disorder, attention deficit hyperactivity disorder in adult patients, and combinations thereof. 
     
     
         23 . The method according any of  claims 19 - 21 , wherein said disease or disorder is suicidality, or suicidal ideation. 
     
     
         24 . The method according to any of  claims 19 - 21 , wherein said disease or disorder is depression. 
     
     
         25 . The method according to any of  claims 19 - 21 , wherein said disease or disorder is major depressive disorder. 
     
     
         26 . The method according to any of  claims 19 - 21 , wherein said disease or disorder is post-partum depression. 
     
     
         27 . The method according to any of  claims 19 - 21 , wherein said disease or disorder is post-traumatic stress disorder. 
     
     
         28 . The method according to any of  claims 19 - 21 , wherein said patient is undergoing treatment with one or more additional agents selected from selective serotonin reuptake inhibitors (SSRI), serotonin agonists, antagonists and modulators, selective norepinephrine reuptake inhibitors (SNRIs). 
     
     
         29 . The method according to any of  claims 19 - 21  wherein said patient is undergoing treatment with one or more additional agents selected from opiate agonists, opiate antagonists, opiate partial agonists, calcium channel antagonists, 5HT, 5-HT 1A  complete or partial receptor agonists or antagonists, 5-HT 2A  complete or partial receptor agonists or antagonists, 5-HT 3  complete or partial receptor agonists or antagonists, sodium channel antagonists, N-methyl-D-aspartate (NMDA) receptor antagonists, COX-2 selective inhibitors, neurokinin receptor 1 (NK1) antagonists, non-steroidal anti-inflammatory drugs (NSAID), selective serotonin reuptake inhibitors (SSRI) and/or selective serotonin and norepinephrine reuptake inhibitors (SSNRI), tricyclic antidepressant drugs, norepinephrine modulators, lithium, valproate, norepinephrine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), alpha-adrenoreceptor antagonists, atypical anti-depressants, benzodiazepines, corticotropin releasing factor (CRF) antagonists, Neurontin (gabapentin) and pregabalin. 
     
     
         30 . The method according to any of  claims 19 - 21  wherein said patient is undergoing treatment with one more additional agents selected from a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), serotonin modulator and stimulator (SMS), serotonin antagonist and reuptake inhibitor (SARI), norepinephrine reuptake inhibitor (NRI), norepinephrine-dopamine reuptake inhibitor (NDRI), tricyclic antidepressant (TCA), tetracyclic antidepressant (TeCA), monoamine oxidase inhibitor (MAOI) and atypical antipsychotic. 
     
     
         31 . The use of a salt, polymorph or composition according to any of  claims 1 - 18  in the manufacture of medicament for the treatment of a disease or disorder according to any of  claims 19 - 30 . 
     
     
         32 . A pharmaceutical formulation comprising a salt according to any of  claim 1 ,  3 ,  4 ,  5 ,  7 ,  9 ,  10 ,  11 ,  13 ,  15 ,  16  or  17  and water. 
     
     
         33 . The pharmaceutical composition according to any of  claim 2 ,  8 ,  12  or  15 , wherein said carrier is water.